Project Summary Obesity is a complex disease, affected by genetics and the environment. Currently over one third of the US population is obese and obesity prevalence in childhood and adolescence is increasing. Diet and lifestyle are major environmental contributors to obesity. Recent work has shown that genetic make-up influences how we respond to diet (e.g., not everyone on a high fat diet (HF) becomes obese) and human genome-wide association studies point to the brain as the major tissue influencing obesity. Not surprisingly, brain function is also altered by diet and influenced by genetics. Understanding the interplay between diet and genetics, including its role in impacting brain function, adiposity, and metabolic health is essential for understanding underlying physiological mechanisms. Such studies are challenging to conduct in human populations. The central premise of this work is that genetic make-up influences response to obesogenic environments, such as a HF diet, and that regulatory brain function plays a major role in this response. Our laboratory uses an outbred rat model, heterogeneous stock (HS) rats, for genetic mapping of adiposity traits. HS rats were created by combining eight inbred founder strains and maintaining them in a way that minimizes inbreeding. We have shown that adiposity is heritable in the HS and have fine-mapped genetic loci and identified both novel and known genes that underlie adiposity. Similar to human GWAS, many of the genes we have identified act in the brain to alter adiposity. Our preliminary data indicates that some HS rats are protected against the negative consequences of a HF diet and that this is likely driven by genetics. The current proposal sets out to use HS rats to understand the interplay between genome, diet and brain transcriptome. The overall hypothesis is that genetic make-up influences susceptibility to diet-induced obesity in HS rats and that this is, in part, driven by altering the brain transcriptome. In Aim 1, we will identify genetic loci that underlie protection from (or susceptibility to) diet-induced obesity in HS rats. In Aim 2, we will identify changes in the brain (specifically hypothalamus and hippocampus) in response to a HF diet as well as map brain transcriptome changes that interact with diet to drive metabolic outcomes in HS rats. We will also create gene networks that respond to diet and influence adiposity. We will use a variety of statistical and genetic techniques, including comparison to human genome wide association studies and the DIETFITS trial, to identify high priority candidate genes which will then be verified using adeno-associated virus over-expression or knock-down, followed by phenotyping to begin to understand underlying gene function. We expect that this work will not only shed light on genetic drivers that lead to protection from the negative consequences of a HF diet, but will also elucidate interactions between diet, genome and brain transcriptome in altering metabolic health. Because this proposal is focused on the central nervous system, we expect that many of these drivers will serve as novel therapeutic targets to impact human behavior, a central feature in the obesity epidemic.